There have been tremendous advances in the field of autoimmunity in the last 20 years, and our understanding of the mechanisms underlying autoimmune disease has grown exponentially. True tolerance is likely to arise not from improved immunosuppression, but from improved understanding of the normal mechanisms that generate and maintain self-tolerance, and the ability to manipulate these mechanisms for the prevention and treatment of autoimmune diseases. The mechanisms of autoimmunity that underlie many diseases are similar, and an integrated multi-specialty approach for evaluating new and emerging therapies would provide the opportunity to integrate knowledge from the various specialties. We have chosen to study therapy of autoimmune disease by blocking co-stimulatory signals with CTLA4Ig and by blocking T cell activation with rapamycin. This strategy has two advantages. First, these are antigen non-specific steps in T cell activation and immune responses. This means that tolerance can be achieved without needing to know the identity of the antigen. Second, restricted delivery of signal two and alteration in cytokine production and profiles are probably involved in normal mechanisms of self-tolerance. Third, by inhibiting T cell activation with rapamycin in addition to costimulatory signal blockade, we may be able to induce long term tolerance by allowing the occurrence of activation induced cell death. The human diseases that our program will focus on are multiple sclerosis (MS), autoimmune diabetes (IDDM), and psoriasis. All are organ specific diseases where T cells appear to be essential in initiating the immune response and lead to the particular disease pathology. Project #1 is the clinical trials project, in which we propose a clinical trial of CTLA4Ig in diabetes, a clinical trial of CTLA4Ig + rapamycin in early MS and describe the available patients and facilities for a potential psoriasis trial. The goals of project #2 are to investigate the role of NK T cells in human diabetes. Project #3 will take a direct approach by cloning T cells and NK T cells from the pancreas and pancreatic lymph nodes of patients with diabetes. The approach of treating autoimmune diseases by preventing T cell activation is timely and has a high likelihood of success. There is a body of evidence including clinical trials supporting the use of CTLA4Ig in autoimmune disease, and also evidence for the synergistic role of rapamycin. The data obtained from the clinical trials and the critical information from the basic science projects will be valuable in getting us closer to our goal of tolerance induction for autoimmune disease.